Researchers Discover BRCA Cancer Cells’ Last Defense

Researchers work to understand why some cells develop chemotherapy resistance.

In a new paper published in Nature Communications, a team led by Saint Louis University researcher Alessandro Vindigni, Ph.D. shares new information about how BRCA-deficient cancer cells operate, interact with chemotherapy drugs and what may be their last-ditch effort to survive. Researchers hope their findings may lead to improved chemotherapy drugs and shed light on why some cells develop chemotherapy resistance.

Vindigni, who is professor of biochemistry and molecular biology at SLU, studies genome integrity, the ability of a cell to faithfully transmit its DNA information on to new cells.

As cells create duplicate copies of their genetic material, a lesion or other obstacle can block DNA replication, potentially derailing a cell’s ability to reproduce. Lesions in DNA can occur as often as 100,000 times per cell per day. They can be the result of normal metabolic activities, like free radicals, as well as exposure to environmental factors such as UV radiation, X-rays and chemical compounds. If a cell’s replication machinery collides with the lesion, a strand break can occur.

When confronted with a lesion, cells have repair strategies, including a tactic called fork reversal. DNA replicates by unzipping its two interwoven strands and making copies of each. As the DNA strands separate and copy, they form a “replication fork.” If these forks run into obstacles like lesions that block their progress, cells perform a maneuver called fork reversal.

Once the damage on the DNA is recognized, DNA replication reverses its course by forming reversed forks. The newly synthesized DNA strands detach from their parental strands and attach to each other. At the same time, the parental strands reconnect, partially zipping up the fork. As a result, the fork transforms into a four-way junction structure, known as a reversed fork. Formation of reversed forks prevents forks from colliding with the replication obstacles, giving time for the damage to be repaired before replication resumes. In previous research, Vindigni and team identified new enzymes that enable cells to resume replication once the DNA lesion has been repaired.

To stop cancer cells, which proliferate by replicating faster than healthy cells, many chemotherapy drugs work by inducing DNA lesions with the hope of blocking replication. While fork reversal strategies help healthy cells survive, they also allow cancer cells to thrive and withstand DNA damaging chemotherapy. The research of Vindigni’s team provided important clues on enzymes that can be targeted to prevent fork reversal and increase chemotherapy sensitivity.

In the current study, Vindigni examined BRCA-deficient cancer cells. Mutations in the BRCA gene are associated with several forms of cancer, including breast, ovarian and prostate cancers.

The healthy cells of people who have BRCA mutations lack one copy of the BRCA gene. If they develop tumors, however, those cells lack both BRCA copies. Scientists used this distinction to develop chemotherapy drugs that take advantage of this difference. The tumor cells are much more susceptible to DNA damaging drugs because they lack both copies, whereas healthy cells aren’t as likely to be affected by the same drugs because they retain one good copy of the gene.

BRCA proteins are known for their role in repairing double strand breaks. They also play a part in “sterilizing” replication forks that have stalled by treatment with DNA damaging agents. A major function of BRCA proteins is to protect these stalled forks and keep them from being degraded. However, the exact structure of the replication forks protected by BRCA proteins remained unknown.

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